The influence of magnesium stearate (MgSt) on blends and finished solid dosage products has presented significant challenges to drug manufacturing, including poor production efficiency and variability in drug disintegration and dissolution. Often, using inappropriate types and amounts of lubricants such as stearic acid, glyceryl behenate, sodium stearyl fumarate, boron nitride, and MgSt as release agents during compression tends to compromise tablets' physical attributes and quality. Such deleterious effects are observed as disturbances in particle–particle interaction and lead to altered powder flow, increased friability, high compression and ejection forces during tableting, and altered dissolution profiles (1–5). The choice, amount, and duration of application of lubricants become important to the finished product's quality and process acceptability. MgSt is widely used as a lubricant in the pharmaceutical and nutraceutical industry. The advantages of MgSt over other lubricants include its high melting temperature, high lubricity at a low concentration, large covering potential, general acceptance as safe, nontoxicity, and its excellent stability profile. It is commercially available mainly in the monohydrate form (MgSt-M) or as a mixture of monohydrate containing a trace of other amorphous and hydrate forms.

Background

Several researchers have studied the influence of MgSt on blending and compression unit operations. Muzzio et al., in trilogy, used ternary mixtures of cellulose, lactose, and acetaminophen to characterize the performance of bin blenders (6). These mixtures were subsequently lubricated with MgSt. Although their predictions about lubrication were based on sample extraction and off-line testing with vibration spectroscopy, they provided a worthy insight into the behavior of MgSt as a lubricant. Wurster, Likitlersuang, and Chen evaluated the influence of MgSt on the Hiestand indices (7). They attributed greater plasticity of lubricated materials to MgSt with resultant downward shift in brittle fracture index. They also hypothesized the existence of predictability in the plasticization effect caused by MgSt. Swaminathan and Kildsig examined the moisture sorption characteristics of commercial MgSt (8). They concluded that dehydration and rehydration of the trihydrate resulted in the formation of the anhydrous form and vice versa.

Luminary work by Rao et al. presented compelling evidence of desirable benefits of the dihydrate form (MgSt-D) for powder lubrication, densification, and flowability (9). In their study, the focus was on a monolithic system (single diluent–MgSt mix), with no evaluation of the impact on blend uniformity, tablet compression, or dissolution. Although their physicochemical characterization alluded to the presence of the dihydrate form in the samples, it failed to clearly identify and isolate the pure form of MgSt-D from other hydrates of MgSt. Their conclusion, however, recommended the use of MgSt possessing some level of the dihydrate form, small particle size, and an absence of agglomerates for blend lubrication. Wu et al. presented substantive evidence of the synthesis, characterization, and isolation of MgSt-D in its pure form (10). Subsequently, Kaufman et al. successfully calibrated the hydrates of MgSt through multivariate analyses using near-infrared (NIR) spectroscopy, thermal gravimetric analysis (TGA), and differential scanning calorimetry (DSC) (11).

The study described in this article introduces the pseudopolymorphic dihydrate form wholly, as an alternative to the monohydrate in pharmaceutical drug development. Briefly, the hydrates differ in particle size, shape, water of hydration, free water, and lubricity. As part of this study, the influence of MgSt hydrates on blends and tablets was conducted using ternary systems comprising active pharmaceutical ingredient (API) with plastically deformable–brittle diluent mix on one hand and plastically deformable–plastically deformable diluent mix on the other. Various ratios of diluents were used to justifiably rule out any ingredient bias that could be attributed to lubricant affinity to one diluent system.

The influence of the pseudopolymorphic MgSt-M and MgSt-D on blends was profiled in real time with in-line thermal effusivity sensors during blending and lubrication steps and with an instrumented tablet press during compression. Although the mechanism is not fully elucidated, it has been hypothesized that when used as a lubricant in a powder mixture, MgSt increases the thermal effusivity of various blends by reducing the interparticulate void spaces, with a resultant densification. Thermal effusivity is a material property that depends on the relationship between thermal conductivity, heat capacity, and density of materials. Hence, increase in material density proportionally increases its thermal effusivity (12–15). It has also been hypothesized that differences in particle morphology and crystalline states of MgSt could influence its lubrication properties in blending processes (9).